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S-phase favours cell responsiveness for Notch activation.

It is unclear how cell fate signalling pathways interact with the cellular machinery that controls the cell cycle. More specifically, little is known about how cell sensitivity to fate signalling mechanisms fluctuates over different phases of the cell cycle. In order to analyse this problem, we looked at whether cell responsiveness to Notch-signalling varies during successive phases of the cell cycle in the bristle lineage. Previous analysis revealed that the G1-phase was essentially absent in bristle lineage cells. Furthermore, the knowledge of the timing of cell cycle phases in these cells allows us to study whether or not they express a differential sensitivity to the Notch pathway during S and G2 cell cycle phases. Using in vivo imaging to define the developmental time points at which the N-pathway was activated, we have shown that cells are more sensitive to Notch when this pathway is activated during the S-phase than during the G2-phase. In addition, this differential N-responsiveness of bristle cells could be modified under experimental conditions that affected the activity of chromatin-remodelling factors. Our experimental evidence suggests that the enhanced sensitivity for N-activation during the S-phase is due to a local de-compacted chromatin state during DNA replication. Thus, we propose that progression through the S-phase overrides local high-order chromatin folding structures in genomic regions essential to implement the response to N-pathway activation. Our results highlight a new mechanism that link Notch-target gene expression and cell cycle during the completion of cell lineages. The main data issued from this work have been published (Remaud S, Audibert A and Gho M (2008) PLoS ONE 3(11) : e3646).